ETIOLOGY OF BLADDER DYSFUNCTION SECONDARY TO PARTIAL OUTLET OBSTRUCTION - CALCIUM DISREGULATION IN BLADDER GENERATION AND THE ABILITY PERFORM WORK

Similar to all smooth muscle, contraction of urinary bladder smooth mu scle depends upon a rise in intracellular free calcium, which results from both calcium influx from extracellular spaces and calcium release from intracellular stores (calcium-induced calcium release [CICR]). R ecent studies from our laboratory demonstrate that one of the major dy sfunctions induced by partial outlet obstruction is a marked reduction in the participation of CICR (from IP3-sensitive and IP3-insensitive sites on the sarcoplasmic reticulum [SR]) during stimulation by both f ield stimulation (neurotransmitter release) and by direct muscarinic s timulation (bethanechol). Experimentally, rabbit urinary bladder funct ion can be evaluated using an isolated whole bladder model. The curren t study utilizes the isolated whole bladder model to compare the effec ts of partial outlet obstruction on the responses to field stimulation and bethanechol with the responses of normal bladders following inhib ition of CICR with the combination of thapsigargin + ryanodine. The pa rameters measured include the magnitude of pressure generation, rate o f pressure generation, time to maximal pressure generation, percent vo lume emptied, rate of emptying, power generation, and work performed ( both total work and work per ml emptied). Partial outlet obstruction r esulted in virtually identical alterations in the responses of the bla dder to stimulation (field stimulation and bethanechol) to that of inh ibition of CICR by thapsigargin + ryanodine. Thus, these studies provi de strong support for our hypothesis that the contractile dysfunctions secondary to partial outlet obstruction are directly related to a mar ked inhibition of the CICR component of the response to both field sti mulation and bethanechol.